When a drug candidate is identified, several challenges lie ahead. Initially, it is necessary to prove that the chosen molecule has the intended pharmacological effect. It is also vital that the safety of the molecule, as well as its therapeutic benefits, are demonstrated. Moreover, the drug developer needs to ensure that the drug substance can be manufactured at industrial scale at a quality that meets expectations.

Drug substance is needed for a large number of safety studies and clinical trials. This poses many challenges for the chemist in terms of quantity and quality and there are many considerations with regards to safety and technical issues that must be taken into account. It is essential that the drug substance manufacturing process is scalable from a technical and economic viewpoint. Additionally, when progressing a drug substance from milligram to kilogram quantities, there are characteristics of the drug substance that can impact formulation.

This article discusses the key challenges facing chemists during the scale-up process for drug substances and sheds light on the different factors that are key to the success of a project.

From milligram method to multi kilogram process: scale-up challenges
As a drug progresses from the candidate drug (CD) selection into, and through the clinical phases, increasingly more drug substance is required. As a result, a milligram preparative method must become a multi kg process, without impacting the quality or the performance of the active pharmaceutical ingredient (API). Put simply, there is an increasing demand for greater quantities, quality and documentation when moving from the pre-clinical phase towards market authorization.

A substantial amount of expertise is required to seamlessly take products from pre-clinical to clinical and then to commercial scale. The routes of synthesis used by medicinal chemists is typically designed for diversity and speed in order to be able to make a lot of variations from an identified hit substance. In this phase the main objective is to improve and optimize the lead substance for its desired primary activity and its physicochemical properties required for later administering of the substance to patients. Thus, with this focus it is not uncommon that the synthetic routes chosen at this stage tend to lack optimal performance with regards to parameters such as economy, safety and robustness; parameters which become increasingly important when performed at a larger scale. As a result, there is a strong likelihood that a synthesis proven within a lab environment will be unsuccessful, or at least unsuitable, when transferred into a production environment.

The time required for the complete process of moving a substance from pre-clinical into early phase clinical development can vary greatly and depends on the length—number of chemical transformations—and complexity of the synthesis. It is important to realize however that the development of a robust process may also be considered as a stepwise process, where development and delivery of the first kilogram for phase I will not have all the characteristics of the final commercial multi kilogram (or ton) manufacturing process. Therefore, typical project and development times will vary greatly, also depending on the ambition, taking anything from a few months to a year, or more. In order to meet intended, and often very short, timescales for early phase API deliveries, it is important to identify the key parameters for successful scale-up and try to predict any problems that may arise as early as possible. These parameters will vary between projects and there are several aspects to consider during API scale-up and transfer to drug product development, described below.

Route scouting
During the early phases, chemists must typically produce from around a few hundred grams of drug substance for safety studies to a few kilograms for first-in-human studies. While there is usually time available to improve the manufacturing process before commercial manufacture, this is the period in which chemists should consider any future actions as making changes may be more difficult or more expensive at a later date. This is because the selected manufacturing process has the potential to affect the purity profile which can subsequently impact the credibility of the safety studies, analytical methods and carryovers.

Route scouting is integral to identifying a practical, safe and cost-effective process for the synthesis of a compound on a large scale. During this process, chemists must determine the scalability of the existing medicinal chemistry route and see if there are any other suitable alternative routes.

The following are examples of questions that should be asked during the route scouting process:

• Is the process safe to scale up?
• Are the raw materials available on a larger scale?
• Are they affordable?
• Are there any technology restrictions with the existing route? High pressure reactions Extreme high or low temperature requirements?
• Are there any valid patents on reagents or process steps that we need to consider?
• Are there any solid intermediates? How are they isolated and purified?
• How is the API isolated and purified?
• Are there any environmental aspects to consider?

In order to evaluate any other promising routes to the target, a thorough review of existing literature is usually carried out during this stage. Often there is a focus on finding ways that will help to reduce the number of synthetic steps to shorten production times to provide a cost-effective and timely delivery. Embedded in this thought process lies all of the above parameters. In addition, the routes finally chosen for further synthetic evaluation and process development may not always be the shortest but are instead dictated by other factors; raw material cost and availability, technology, safety, etc.

Additionally, a greater number of synthetic steps may sometimes be required to ensure that there are enough GMP steps within the process to meet regulatory requirements. Starting material selection is one of the primary regulatory topics being discussed across the pharmaceutical industry currently. At the start of a project, correct regulatory starting material (RSM) is essential in order to prevent starting material redefinition. Material redefinition is a costly and time-consuming process which can often result in complete process remodeling.

Although not necessarily part of the route scouting process as such, the solid-state properties and characteristics of the final API is an extremely important aspect to take into consideration at an early stage, and especially so if the API is intended for solid dosage forms. The solid-state properties of the API will influence important factors such as stability, solubility, formulation and process robustness. A careful evaluation and selection of a proper salt form and polymorph at an early stage is therefore strongly recommended.   
 
Collaboration
When scaling a drug substance, effective collaboration is a necessity. With various experts such as process chemists and analytical chemists involved in the development of the drug substance, but also formulation scientists in the interface and transfer into drug product development, a clear chain of communication is crucial to the success of a project. Cross-functional collaboration enables the team to work with a clear and common goal; thus, meeting clinical plans and strict timeframes. This collaboration includes both transfer of knowledge but also actual test batch material for hands-on laboratory work.

The start date of clinical studies is an important aspect of the scale-up process. For example, it is important that the clinical trial material is manufactured in a timely manner, which also requires a timely supply of the GMP drug substance. The delivery of these materials is reliant upon effective collaboration. 

An integrated approach
Drug substance development and manufacturing should also consider the intended drug product in order to make the transition into drug product development as seamless as possible. As such, many drug developers are recognizing the benefits of working with contract development and manufacturing organizations (CDMOs) that have experience and knowledge in the development and manufacture of both drug substances and drug products.

In addition, using a partner that understands the whole process, from the pre-clinical stage through to commercial manufacture, can help to reduce time and manage complexity. Furthermore, amongst several other benefits, CDMOs with a comprehensive offering tend to have multi-purpose plants which allows the manufacture of several drug substances, at one time. Thus, their facilities are usually equipped for diversity in order to effectively react to different needs. In addition, and perhaps more importantly, CDMOs offering a variety of batch sizes can also accommodate seamless transfer of the project into larger vessels as the project progresses through the clinical phases. As a result of this flexibility, challenges and timelines can be overcome more efficiently. 

Conclusion
There are several challenges involved in the scale-up process of a drug substance. As such, it is important to ensure that the necessary steps and evaluations are carried out in order to manage complexities and reduce timelines. Taking an integrated approach to drug substance and drug product development can help to overcome issues and speed up timelines. As such, the popularity of working with CDMOs that offer end-to-end solutions and that can develop drug substances with the end goal in mind is increasing. 

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Anders Högdin is senior sales director at Recipharm. He joined Recipharm in 2015 to head the business development and sales team within development services in Europe. With a wealth of experience in early process development of drug substance working within the CDMO industry, he also holds an MSc in chemistry and a PhD in organic chemistry.